The present invention is directed to novel 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful in the treatment of disorders and conditions mediated by the ORL-1 G-protein coupled receptor. More particularly, the compounds of the present invention are useful in the treatment of disorders and conditions such as anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition.
The ORL-1 (orphan opioid receptor) G-protein coupled receptor, also known as the nociceptin receptor, was first reported in 1994, and was discovered based on its homology with the classic delta-, mu-, and kappa-opioid receptors. The ORL-1 G-protein coupled receptor does not bind opioid ligands with high affinity. The amino acid sequence of ORL-1 is 47% identical to the opioid receptors overall, and 64% identical in the transmembrane domains. (Nature, 1995, 377, 532.)
The endogenous ligand of ORL-1, known as nociceptin, a highly basic 17 amino acid peptide, was isolated from tissue extracts in 1995. It was named both nociceptin, because it increased sensitivity to pain when injected into mouse brain, and orphanin FQ (OFQ) because of the terminal phenylalanine (F) and glutamine (O) residues that flank the peptide on either side. (WO97/07212)
Nociceptin binding to ORL-1 receptors causes inhibition of cAMP synthesis, inhibition of voltage-gated calcium channels, and activation of potassium conductance. In vivo, nociceptin produces a variety of pharmacological effects that at times oppose those of the opioids, including hyperalgesia and inhibition of morphine-induced analgesia. Mutant mice lacking nociceptin receptors show better performance in learning and memory tasks. These mutant mice also have normal responses to painful stimuli.
The ORL-1 receptor is widely distributed/expressed throughout the human body, including in the brain and spinal cord. In the spinal cord, the ORL-1 receptor exists in both the dorsal and ventral horns, and precursor mRNA has been found in the superficial lamina of the dorsal horn, where primary afferent fibers of nociceptors terminate. Therefore, the ORL-1 has an important role in nociception transmission in the spinal cord. This was confirmed in recent studies wherein nociceptin, when given to mice by i.c.v. injection, induced hyperalgesia and decreased locomotor activity. (Brit. J. Pharmacol. 2000, 129, 1261.)
Adam, et al., in U.S. Pat. No. 6,071,925 (and in EP 0856514) disclose 1,3,8-triazaspiro[4,5]decan-4-one derivatives, agonists and/or antagonists of the OFQ receptor. More recently, Higgins, et. al., in European Forum of Neuroscience 2000, Brighton, U.K., Jun. 24-28, 2000, Poster 077.22 disclosed, 8-[(1R,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one useful as a cognition enhancers. Adam et al., in EP 921125-A1 disclose 1,3,8-triazaspiro[4.5]decan-4-one derivatives, agonists and/or antagonists of the OFQ receptor.
Ito, et al., in EP 0997464 disclose 1,3,8-triazaspiro[4.5]decan-4-one compounds as ORL-1 receptor agonists.
Watson, et al., in WO 99/59997 disclose 1,3,8-triazaspiro[4.5]decan-4-ones with high affinity for opioid receptor subtypes, useful for the treatment of migraine, type II diabetes, sepsis, inflammation, incontinence and/or vasomotor disturbance.
JP2000169476, assigned to Banyu Pharmaceutical Co., Ltd, disclose 4-oxoimidazolidine-5-spiro-nitrogen containing heterocyclic compounds which inhibit binding of nociceptin to the ORL1 receptor.
We now describe novel small molecule modulators of the ORL-1 receptor, useful for the treatment of disorders and conditions mediated by the ORL-1 receptor, such as anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition.
The present invention is directed to compounds of the general formula 
wherein
R1 is selected from the group consisting of hydrogen, C1-6alkyl, aryl and aralkyl;
wherein the aryl or aralkyl group is optionally substituted with one to four substituents independently selected from halogen, C1-6alkyl, halogenated C1-6alkyl, C1-6alkoxy, nitro, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, C1-6alkylsulfonyl, amido, (C1-6alkyl)amido, di(C1-6alkyl)amido, sulfonyl, aminosulfonyl, (C1-6alkyl)aminosulfonyl, di(C1-6alkyl)aminosulfonyl or C3-8cycloalkyl;
R2 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyaminoC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkoxycarbonylC1-6alkyl, aryl, C3-8cycloalkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl, C1-6aralkyl, carbocyclylC1-6alkyl, heteroarylC1-6alkyl, heterocycloalkylC1-6alkyl and phthalimidoylC1-6alkyl;
wherein the alkyl group is optionally substituted with one to two substituents independently selected from hydroxy, carboxy, cyano, amino, C1-6alkylamino, di(C1-6alkyl)amino, hydroxyC1-6alkylamino, aminoC1-6alkylamino, C1-6alkylaminoC1-6alkylamino or di(C1-6alkyl)aminoC1-6alkylamino,
wherein the aryl, cycloalkyl, carbocyclyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to four substituents independently selected from halogen, C1-6alkyl, halogenated C1-6alkyl, C1-6alkoxy, nitro, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, C1-6alkylsulfonyl, amido, (C1-6alkyl)amido, di(C1-6alkyl)amido, sulfonyl, aminosulfonyl, (C1-6alkyl)aminosulfonyl, di(C1-6alkyl)aminosulfonyl or C1-4alkoxycarbonyl;
a is an integer from 0 to 2;
R3 is selected from the group consisting of C1-4alkyl and hydroxy C1-4alkyl;
n is an integer from 0 to 1;
X is selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-4alkyl-O and C2-4alkyl-S;
wherein the alkyl group is optionally substituted with one to two substituents independently selected from fluoro, C1-6alkyl, fluorinated C1-6alkyl, C1-6alkoxy, nitro, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, C1-6alkylsulfonyl, amido, (C1-6alkyl)amido, di(C1-6alkyl)amido, sulfonyl, aminosulfonyl, (C1-6alkyl)aminosulfonyl or di(C1-6alkyl)aminosulfonyl;
and wherein X is C2-4alkyl-O or C2-4alkyl-S, the X group is incorporated into the molecule such that the C2-4alkyl is bound directly to the piperidine portion of the molecule; 
is selected from the group consisting of phenyl, a five membered heteroaryl and a six membered heteroaryl;
b is an integer from 0 to 1;
R4 is selected from the group consisting of aryl, C3-8cycloalkyl, partially unsaturated carbocyclyl, heteroaryl and heterocycloalkyl;
c is an integer from 0 to 3;
R5 is selected from the group consisting of halogen, C1-6alkyl, halogenated C1-6alkyl, C1-6alkoxy, nitro, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, C1-6alkylsulfonyl, amido, (C1-6alkyl)amido, di(C1-6alkyl)amido, sulfonyl, aminosulfonyl, (C1-6alkyl)aminosulfonyl or di(C1-6alkyl)aminosulfonyl;
m is an integer from 0 to 1;
Y is selected from the group consisting of C1-4alkyl, C2-4alkenyl, O, S, NH, N(C1-4alkyl), C1-6alkyl-O, C1-6alkyl-S, Oxe2x80x94C1-6alkyl and Sxe2x80x94C1-6alkyl-S;
R6 is selected from the group consisting of aryl, partially unsaturated carbocyclyl, C3-8cycloalkyl, heteroaryl, heterocycloalkyl and benzoyloxyphenyl;
wherein the aryl, partially unsaturated carbocyclyl, C3-8cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to four substituents independently selected from halogen, hydroxy, C1-6alkyl, halogenated C1-6alkyl, C1-6alkoxy, nitro, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, C1-6alkylsulfonyl, amido, (C1-6alkyl)amido, di(C1-6alkyl)amido, sulfonyl, aminosulfonyl, (C1-6alkyl)aminosulfonyl, di(C1-6alkyl)aminosulfonyl or triphenylmethyl;
provided that when a is 0, R1 is phenyl, R2 is hydrogen, n is 1, X is CH2, 
is phenyl, b is 0, c is 0 and m is 0, then R6 is selected from the group consisting of partially unsaturated carbocyclyl, C3-8cycloalkyl, heteroaryl, heterocycloalkyl, benzoyloxyphenyl and substituted aryl; (i.e. not aryl, not phenyl)
wherein the aryl, partially unsaturated carbocyclyl, C3-8cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to four substituents independently selected from halogen, C1-6alkyl, halogenated C1-6alkyl, C1-6alkoxy, nitro, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, C1-6alkylsulfonyl, amido, (C1-6alkyl)amido, di(C1-6alkyl)amido, sulfonyl, aminosulfonyl, (C1-6alkyl)aminosulfonyl, di(C1-6alkyl)aminosulfonyl or triphenylmethyl;
provided further that when a is 0, R1 is phenyl, R2 is hydrogen, n is 1, X is C1-3alkyl, 
is phenyl, b is 0, c is 0 and m is 0, then R6 is not substituted thiazolyl; wherein the substituent on the thiazolyl is selected from amino, C1-4alkylamino, di(C1-4alkyl)amino or nitro;
provided further that when a is 0, R1 is phenyl, R2 is hydrogen, n is 1, X is CH2, b is 0, c is 0 and m is 0, and R6 is phenyl, then 
is not imidazolyl or pyrrolyl;
and pharmaceutically acceptable salts thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating disorders and conditions mediated by the ORL-1 receptor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is a method of treating a condition selected from the group consisting of anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) anxiety, (b) depression, (c) substance abuse (d) neuropathic pain, (e) acute pain, (f) migraine, (g) asthma and for (h) improved cognition, in a subject in need thereof.
The present invention provides 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of disorders and conditions mediated by the ORL-1 receptor. More particularly, the compounds of the present invention are of the formula (I) 
wherein R1, R2, a, R3, n, X, 
b, R4, c, R5, m, Y and R6 are as herein defined, and pharmaceutically acceptable salts thereof.
In an embodiment of the invention R1 is selected from the group consisting of hydrogen, C1-6alkyl, aryl, substituted aryl and aralkyl. Preferably R1 is selected from the group consisting of C1-4alkyl, aryl, substituted aryl and aralkyl, wherein the aryl group is substituted with a substituent selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethyl and C5-6cycloalkyl. More preferably, R1 is selected from the group consisting of n-propyl, phenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyclopentylphenyl, 3-bromophenyl, 3-chlorophenyl, 4-chloro-3-methylphenyl and 4-fluoro-3,5-dimethylphenyl.
In an embodiment of the invention R2 is selected from the group consisting of hydrogen, C1-6alkyl, substituted C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyaminoC1-6alkyl, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, aminocarbonylC1-6alkyl, carboxyC1-6alkyl, C1-6alkoxycarbonylC1-6alkyl, aryl, substituted aryl, C3-8cycloalkyl, substituted C3-8cycloalkyl, partially unsaturated carbocyclyl, substituted partially unsaturated carbocyclyl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, C1-6aralkyl, carbocyclylC1-6alkyl, heteroarylC1-6alkyl, heterocycloalkylC1-6alkyl and phthalimidoylC1-6alkyl. Preferably, R2 is selected from the group consisting of hydrogen, C1-4alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl, aminocarbonylC1-4alkyl, carboxyC1-4alkyl, C1-4alkoxycarbonylC1-4alkyl, phthalimidoylC1-4alkyl and substituted oxazolylC1-4alkyl. More preferably, R2 is selected from the group consisting of hydrogen, methyl, cyanomethyl, 2-hydroxyethyl, aminoethyl, dimethylaminoethyl, diethylaminoethyl, aminocarbonylmethyl, carboxymethyl, methoxycarbonylmethyl, phthalimidoylethyl and 4-methoxycarbonyl-5-oxazolylmethyl.
In an embodiment of the invention a is an integer from 0 to 2, preferably a is an integer from 0 to 1. Preferably, R3 is selected from the group consisting of C1-4alkyl and hydroxyC1-4alkyl.
In a preferred embodiment of the invention n is 1.
In an embodiment of the invention, X is selected from the group consisting of C1-6alkyl, substituted C1-6alkyl, C2-6alkenyl, C2-4alkyl-O and C2-4alkyl-S. Preferably, X is selected from the group consisting of C1-6alkyl, substituted C1-6alkyl, C2-4alkyl-O and C2-4alkyl-S. More preferably, X is selected from the group consisting of C1-4alkyl and C2-4alkyl-O, most preferably, C1alkyl (CH2), C2alkyl (CH2CH2), C3alkyl (CH2CH2CH2), C4alkyl (CH2CH2CH2CH2) and C2alkyl-O (CH2CH2xe2x80x94O).
Wherein X is C2-4alkyl-O or C2-4alkyl-S group, X is incorporated into the molecule such that the C2-4alkyl is bound directly to the piperidine portion of the molecule
In an embodiment of the invention 
is selected from the group consisting of phenyl, a five membered heteroaryl and a six membered heteroaryl, preferably 
is selected from phenyl, a five membered heteroaryl other than imidazolyl or pyrrolyl and a six membered heteroaryl. More preferably, 
is selected from the group consisting of phenyl, furyl, thienyl, pyridyl and pyrazolyl.
In an embodiment of the invention b is 0. In another embodiment of the invention c is an integer from 0 to 2. In yet another embodiment of the invention c is an integer from 0 to 1. In yet another embodiment of the invention c is 0.
In an embodiment of the invention R5 is selected from the group consisting of halogen, fluorinatedC1-4alkyl and C1-4alkyl. Preferably R5 is selected from the group consisting of halogen, methyl and trifluoromethyl. More preferably R5 is selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl. More preferably still R5 is selected from the group consisting of fluoro, methyl and trifluoromethyl, more preferably still R5 is selected from fluoro or methyl.
In an embodiment of the invention, Y is selected from the group consisting of C1-4alkyl, C2-4alkenyl, O, S, NH, N(C1-4alkyl), C1-6alkyl-O, C1-6alkyl-S, Oxe2x80x94C1-6alkyl and Sxe2x80x94C1-6alkyl-S. Preferably, Y is selected from the group consisting of O, C1-4alkyl-O, C2-4alkenyl and C1-4alkyl. More preferably, Y is selected from the group consisting of O, CH2xe2x80x94O, CHxe2x95x90CH and CH2.
In an embodiment of the invention, R6 is selected from the group consisting of aryl, substituted aryl, partially unsaturated carbocyclyl, substituted partially unsaturated carbocyclyl, C3-8cycloalkyl, substituted C3-8cycloalkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl. Preferably, R6 is selected from the group consisting of aryl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl, hydroxyphenyloxymethyl and benzoyloxyphenyl, wherein the aryl, heteroaryl or heterocycloalkyl is optionally substituted with one to two substituents independently selected from halogen, acetyl, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano, nitro, oxo, t-butoxycarbonyl and triphenylmethyl. More preferably, R6 is selected from the group consisting of 3-methylphenyl, 4-methylphenyl, 3,5-dichlorophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 3-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 1-naphthyl, 2-naphthyl, 2-(1-Boc-pyrrolyl), 1-(1,2,3,4-tetrahydronaphthyl), phenyl, 4-dimethylaminophenyl, 4-pyridyl, 3-quinolinyl, 2-benzothienyl, 2-benzofuryl, 5-indolyl, 2-thiazolyl, 5-chloro-2-thienyl, 5-acetyl-2-thienyl, 5-methyl-2-thienyl, 5-cyano-2-thienyl, 4-methyl-2-thienyl, 3,5-dimethyl-4-isoxazolyl, 3-pyridyl, 4-chlorophenyl, 1-(5,6,7,8-tetrahydronaphthyl), 4-hydroxyphenyloxymethyl, 1-piperidinyl, 1-(1,2,3,4-tetrahydroquinolinyl), 2-(1,2,3,4-tetrahydroisoquinolinyl), 1-pyrrolidinyl, 1-phthalimidoyl, 1-imidazolyl, 3-imidazolyl, 1-triphenylmethyl-3-imidazolyl, 1-(2-piperidinoyl), 3-chlorophenyl, 4-nitrophenyl, 4-bromophenyl, 4-chlorophenyl and benzoyloxyphenyl. Most preferably, R6 is selected from the group consisting of 3-methylphenyl, 4-methylphenyl, 3,5-dichlorophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 3-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 1-naphthyl, 2-naphthyl, 2-(1-Boc-pyrrolyl), 1-(1,2,3,4-tetrahydronaphthyl), phenyl, 4-dimethylaminophenyl, 4-pyridyl, 3-quinolinyl, 2-benzothienyl, 2-benzofuryl, 5-indolyl, 5-chloro-2-thienyl, 5-acetyl-2-thienyl, 5-methyl-2-thienyl, 5-cyano-2-thienyl, 4-methyl-2-thienyl, 3,5-dimethyl-4-isoxazolyl, 3-pyridyl, 4-chlorophenyl, 1-(5,6,7,8-tetrahydronaphthyl), 4-hydroxyphenyloxymethyl, 1-piperidinyl, 1-(1,2,3,4-tetrahydroquinolinyl), 2-(1,2,3,4-tetrahydroisoquinolinyl), 1-pyrrolidinyl, 1-phthalimidoyl, 1-imidazolyl, 3-imidazolyl, -triphenylmethyl-3-imidazolyl, 1-(2-piperidinoyl), 3-chlorophenyl, 4-nitrophenyl, 4-bromophenyl 4-chlorophenyl and benzoyloxyphenyl.
In an embodiment of the invention R6 is not thiazolyl or substituted thiazolyl. In another embodiment of the invention, 
is not imidazolyl or pyrrolyl.
As used herein, xe2x80x9chalogenxe2x80x9d shall mean chlorine, bromine, fluorine and iodine.
As used herein, the term xe2x80x9calkylxe2x80x9d, whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, xe2x80x9clowerxe2x80x9d when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
As used herein, unless otherwise noted, xe2x80x9calkoxyxe2x80x9d shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, unless otherwise noted, xe2x80x9carylxe2x80x9d shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.
As used herein, unless otherwise noted, xe2x80x9caralkylxe2x80x9d shall mean any lower alkyl group substituted with an aryl group such as phenyl, naphthyl and the like. For example, benzyl (phenylmethyl), phenylethyl, phenylpropyl, naphthylmethyl, and the like.
As used herein, unless otherwise noted, the term xe2x80x9ccycloalkylxe2x80x9d shall mean any stable 3-8 membered monocyclic, carbon based, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, unless otherwise noted, the term xe2x80x9ccarbocyclylxe2x80x9d shall mean any four to fourteen membered monocyclic or bicyclic, carbon based ring structure. Similarly, unless otherwise noted, the term xe2x80x9cpartially unsaturated carbocyclylxe2x80x9d shall mean any four to fourteen membered monocyclic or bicyclic, carbon based ring structure containing at least one unsaturated bond. Suitable examples include 1,2,3,4-tetrahydronaphthyl, cyclohexen-1-yl, and the like.
As used herein, unless otherwise noted, xe2x80x9cheteroarylxe2x80x9d shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine or ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like. Preferred heteroaryl groups include thienyl, pyridyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, indolyl, isoindolyl, quinolinyl, benzofuryl and benzothienyl.
As used herein, the term xe2x80x9cheterocycloalkylxe2x80x9d shall denote any five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine to ten membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
Examples of suitable heterocycloalkyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofury, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, and the like. Preferred heterocycloalkyl groups include pyrrolidinyl, piperidinyl, imidazolyl, 1,2,3,4-tetrahydroisoquinolinyl and 1,2,3,4-tetrahydroquinolinyl.
As used herein, the notation xe2x80x9c*xe2x80x9d shall denote the presence of a stereogenic center.
When a particular group is xe2x80x9csubstitutedxe2x80x9d (e.g., alkyl, aryl, carbocyclyl, heterocycloalkyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
Suitable alkyl substituents include hydroxy, carboxy, cyano, amino, C1-6alkylamino, di(C1-6alkyl)amino, hydroxyC1-6alkylamino, aminoC1-6alkylamino, C1-6alkylaminoC1-6alkylamino and di(C1-6alkyl)aminoC1-6alkylamino.
Suitable cycloalkyl, aryl, carbocyclyl, heteroaryl and heterocycloalkyl substituents include halogen, hydroxy, C1-6alkyl, halogenated C1-6alkyl, C1-6alkoxy, nitro, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, C1-6alkylsulfonyl, amido, (C1-6alkyl)amido, di(C1-6alkyl)amido, sulfonyl, aminosulfonyl, (C1-6alkyl)aminosulfonyl, di(C1-6alkyl)aminosulfonyl and C3-8cycloalkyl. Preferably, the cycloalkyl, aryl, carbocyclyl, heteroaryl and heterocycloalkyl substituents include halogen, C1-6alkyl, halogenated C1-6alkyl, C1-6alkoxy, nitro, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, C1-6alkylsulfonyl, amido, (C1-6alkyl)amido, di(C1-6alkyl)amido, sulfonyl, aminosulfonyl, (C1-6alkyl)aminosulfonyl and di(C1-6alkyl)aminosulfonyl.
With reference to substituents, the term xe2x80x9cindependentlyxe2x80x9d means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a
xe2x80x9cphenylC1-C6alkylcarbonylaminoC1-C6alkylxe2x80x9d substituent refers to a group of the formula 
Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Compounds of formula (I) wherein n is an integer from 0 to 1, m is an integer from 0 to 1, Y is selected from C2-4alkenyl and R6 is aryl or heteroaryl, may be prepared according to the process outlined in Scheme 1. 
More particularly, a compound of formula (II), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, in the presence of a base such as DIPEA, TEA, pyridine, Na2CO3, K2CO3, and the like, wherein the base is present in an amount of at least one equivalent, in an organic solvent such as acetonitrile, DMF, DMSO, NMP, and the like, preferably at an elevated temperature, to yield the corresponding compound of formula (IV).
When the base is an inorganic base such as Na2CO3, K2CO3, and the like, the compound of formula (II) is reacted with the compound of formula (III) in an aprotic solvent such as DMF, DMSO, NMP, and the like.
The compound of formula (IV) is reacted with a suitably substituted boronic acid, a compound of formula (V), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, and the like, in the presence of a base such as Na2CO3, NaHCO3, K3PO4, and the like, in a non-protic organic solvent or mixture thereof such as toluene, toluene/ethanol, DME, DMF, and the like, to yield the corresponding compound of formula (Ia).
Compounds of formula (I) wherein n is an integer from 0 to 1, m is 0 and R6 is aryl or heteroaryl, may alternatively be prepared according to the process outlined in Scheme 2. 
Specifically, a suitably substituted bromoaldehyde, a compound of formula (VI), a known compound or compound prepared by known methods, is reacted with a suitably substituted boronic acid, a compound of formula (VII), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, and the like, in the presence of a base such as Na2CO3, NaHCO3, K3PO4, and the like, in a non-protic organic solvent or mixture thereof such as toluene, toluene/ethanol, DME, DMF, benzene, and the like, to yield the corresponding compound of formula (VIII).
The compound of formula (VIII) is reacted with a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, in the presence of a reducing agent such as sodium triacetoxyborohydride (Na(OAc)3BH), sodium cyanoborohydride (NaCNBH3), and the like, optionally in the presence of an acid such as acetic acid (AcOH), and the like, in an organic solvent such as DCE, THF, acetonitrile, and the like, to yield the corresponding compound of formula (Ib).
The compound of formula (VIII) may alternatively be prepared according to the process outlined in Scheme 3. 
Accordingly, a suitably substituted compound of formula (IX), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, and the like, in the presence of a base such as aqueous NaHCO3, Na2CO3, K3PO4, and the like, in an organic solvent such as DME, DMF, toluene, benzene, and the like, to yield the corresponding compound of formula (VIII).
Compounds of formula (I) wherein n is 1, X is CH2, m is 1, Y is O and R6 is aryl or heteroaryl, may be prepared according to the process in Scheme 4. 
More particularly, for compounds of formula (I) wherein Y is O and R6 is bound to the O through a tetrahedral carbon (i.e. a carbon atom that is not part of a unsaturated bond), a compound of formula (XI), a known compound or compound prepared by known methods, is reacted with a suitably substituted alcohol, a compound of formula (XII), a known compound or compound prepared by known methods, in the presence of an activating agent such as tributylphosphine, triphenylphosphine, diphenyl-2-pyridylphosphine, and the like, in an anhydrous organic solvent such as benzene, THF, DCM, and the like, (via a Mitsunobu reaction) in the presence of a dehydrating agent such as 1,1xe2x80x2-(azodicarbonyl)dipiperidine, diethylazodicarboxylate, diisopropylazodicarboxylate, and the like, to yield the corresponding compound of formula (XIII).
For compounds of formula (I) wherein Y is O and R6 is bound to the O through a carbon atom that is part of a double bond (i.e. a carbon atom which is part of an aryl, heteroaryl or other unsaturated group), the compound of formula (XI) is reacted with a suitably substituted boronic acid, a compound of formula (VII), a known compound or compound prepared by known methods, in the presence of a catalyst such as copper (II) acetate, and the like, in the presence of an base such as TEA, pyridine, and the like, in the presence of molecular sieves, preferably 4 Angstrom molecular sieves, in an organic solvent such as DCM, DCE, and the like, at ambient temperature, to yield the corresponding compound of formula (XIII).
Alternatively, the compound of formula (XIII) may be prepared by reacting a compound of formula (XI) wherein the hydroxy (OH) group is replaced with a fluoro, bromo or triflate with a compound of formula (XII), as defined above, in the presence of a base such as K2CO3, sodium carbonate, sodium bicarbonate, and the like, in a dipolar aprotic solvent such as (CH3)2NCOCH3, DMF, DMSO, and the like.
The compound of formula (XIII) is reacted with a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, and the like, in an organic solvent such as DCE, THF, acetonitrile, and the like, to yield the corresponding compound of formula (Ic).
One skilled in the art will recognize that compounds of formula (I) wherein m is 1 and Y is S may similarly be prepared according to the process outlined above with appropriate selection and substitution of suitably substituted starting materials.
One skilled in the art will recognize that compounds of formula (I) wherein m is 1 and Y is NH or N(C1-4alkyl) may similarly be prepared according to the process outlined in Scheme 1 with suitable selection and substitution of suitably substituted starting materials (i.e. amination of the arylbromide compound of formula (IV) by reacting with a suitably substituted amine of the formula R6xe2x88x92NH2, in the presence of palladium (0) catalysts (e.g. Buckwald reaction) as described in Accts. Chem. Res. 1998, 31, 805.).
Compounds of formula (I) wherein n is an integer from 0 to 1, m is an integer from 0 to 1, Y is selected from C2-4alkenyl and R6 is aryl or heteroaryl, may alternatively be prepared according to the process outlined in Scheme 5. 
Accordingly, a suitably substituted compound of formula (XIV), a known compound or compound prepared by known methods, is reacted with a suitably substituted boronic acid, a compound of formula (V), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, and the like, in the presence of a base such as aqueous NaHCO3, Na2CO3, K3PO4, and the like, in an organic solvent such as DME, benzene, and the like, to yield the corresponding compound of formula (XV).
The compound of formula (XV) is reacted with methanesulfonyl chloride, in the presence of an organic base such as TEA, DIPEA, N-methylmorpholine, and the like, in an aprotic organic solvent such as DCM, THF, acetonitrile, CHCl3, and the like, to yield the corresponding compound of formula (XVI).
The compound of formula (XVI) is reacted with a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, pyridine, and the like, in an aprotic organic solvent such as DCE, THF, acetonitrile, NMP, and the like, to yield the corresponding compound of formula (Id).
Compounds of formula (I) wherein n is 1, X is CH2, 
is phenyl, m is 1, Y is xe2x80x94CH2xe2x80x94 and the xe2x80x94(Y)mxe2x80x94R6 group is bound at the 3 or 4 position (not the 2 position), may be prepared according to the process outlined in Scheme 6. 
More specifically, a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, is reacted with 1,4- or 1,3-bis-(chloromethyl)benzene, a known compound, in the presence of an organic base such as DIPEA, TEA, N-methylmorpholine, and the like, in an organic solvent such as NMP, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XVII), wherein the chloromethyl is bound at the 4- or 3-position, respectively.
The compound of formula (XVII) is reacted with a suitably substituted compound of formula (XVIII), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, K2CO3, Na2CO3, and the like, in an organic solvent such as NMP, DMF, THF, and the like, to yield the corresponding compound of formula (Ie), wherein the xe2x80x94(Y)mxe2x80x94R6 group is bound at the 4 or 3 position, respectively,
Alternatively, the compound of formula (II) may be reacted with 1,3- or 2,6-di(chloromethyl)pyridyl, to yield the corresponding compound wherein the 
portion of the molecule is a suitably substituted pyridylmethyl rather than a suitably substituted benzyl.
Alternatively, compounds of formula (I) (X)n is CH2, 
is phenyl, m is 1, Y is xe2x80x94CH2xe2x80x94 and the xe2x80x94(Y)mxe2x80x94R6 group is bound at the 3 or 4 position (not the 2 position), may be prepared according to the process outlined in Scheme 7. 
Accordingly, 1,2-, 1,3 or 1,4-substituted bischloromethyl benzene, a known compound is reacted with a suitably substituted compound of formula (XVIII), a known compound or compound prepared by known methods, in an organic solvent such as THF, DMSO, DMF, and the like, in the presence of a base such as NaH, Na2CO3, K2CO3, N-butyl lithium, and the like, to yield a mixture of the mono- and di-substituted benzene compounds of formula (XIX) and (XX).
The mono-substituted compound of formula (XIX) is preferably isolated and then reacted with a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, in the presence of an organic base such as DIPEA, TEA, pyridine, N-methylmorpholine, and the like, in an organic solvent such as NMP, THF, DMF, and the like, to yield the corresponding compound of formula (If).
Compounds of formula (I) wherein n is 0 may alternatively be prepared by adapting the process described in J. Org. Chem. 1997, 62, 1264, and references cited therein. More particularly, the compounds of formula (I) wherein n is 0 may be prepared according to the process outlined in Scheme 8. 
Accordingly, a suitably substituted compound of formula (XXI), wherein each Q is independently selected from xe2x80x94Br, xe2x80x94Cl or xe2x80x94OSO2CF3, a known compound or compound prepared by known methods is reacted with a suitably substituted boronic acid, a compound of formula (V), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, and the like, in an organic solvent such as DME, DMF, toluene, and the like, to yield the corresponding compound of formula (XXII).
The compound of formula (XXII) is reacted with a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd2(dba)3, Pd2(OAc)2, and the like, in the presence of a case such as KO-t-Bu, NaO-t-Bu, K3, PO4, and the like, in an organic solvent such as THF, DME, toluene, and the like, to yield the corresponding compound of formula (Ig).
Alternatively, a suitably substituted compound of formula (XXI), wherein each Q is independently selected from, xe2x80x94Br, xe2x80x94Cl or xe2x80x94OSO2CF3, a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, in the presence of a catalysts such Pd2(dba)3, Pd2(OAc)2, and the like, in the presence of a case such as KO-t-Bu, NaO-t-Bu, K3, PO4, and the like, in an organic solvent such as THF, DME, toluene, and the like, to yield the corresponding compound of formula (XXIII)
The compound of formula (XXIII) is reacted with a suitably substituted boronic acid, a compound of formula (V), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, and the like, in the presence of a base such as Na2CO3, NaHCO3, and the like, in an organic solvent such as DME, DMF, toluene, and the like, to yield the corresponding compound of formula (Ig).
Compounds of formula (I) wherein R1 and R2 are varied, may be prepared from suitably substituted starting materials according to the processes disclosed in U.S. Pat. No. 3,155,699 (Issued Nov. 3, 1964) and/or in PCT Application WO 99/59997.
Compounds of formula (I) wherein R2 is selected from carboxy substituted C1-6alkyl, aminoC1-6alkyl, aminocarbonylC1-6alkyl or C1-6alkylcarbonylC1-6alkyl, wherein the amino portion of the R2 group may be optionally substituted with one or two C1-6alkyl groups, may be prepared according to the process outlined in Scheme 9. 
Accordingly, a suitably substituted compound of formula (Ih), (a compound of formula (I) wherein R2 is hydrogen), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XXIV), a known compound or compound prepared by known methods, in the presence of a strong base such as NaH, KH, sodium trimethylsilylamide, and the like, in an organic solvent such as DMF, NMP, THF, and the like, to yield the corresponding compound of formula (I).
Alternatively, the compound of formula (Ih) is reacted with a compound of formula (XXIV), wherein the hydroxy, carboxy or amino portion of the R2 group is protected, followed by de-protection by known methods, to yield the corresponding compound of formula (I).
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
Following the procedures described herein, selected compounds of the present invention were prepared as listed in Table 1-10.
The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 5 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The method of treating disorders mediated by the ORL-1 receptor described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 1 mg and 1000 mg, preferably about 10 to 500 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders mediated by the ORL-1 receptor is required.
The daily dosage of the products may be varied over a wide range from 5 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.2 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.5 mg/kg to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.